PROJECT SUMMARY/ABSTRACT Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease that involves the combination of both genetic and environmental risk factors for disease in humans. This disease afflicts over 3 million people worldwide, and there is currently no cure for SLE. Recently, I have developed a novel mouse model that has a knockin of a human SLE-associated gene variant (GV) in the mismatch repair gene MSH6. Interestingly, preliminary data indicate that mice homozygous for the MSH6 GV have significantly increased serum titers of anti-nuclear antibodies, a hallmark criterion of SLE, as compared to wildtype mice. The main objective of this study is to analyze two human-associated factors, one environmental and the other genetic, to understand the underlying mechanism of SLE pathogenesis. Importantly, this study is significant because the use of two human- associated factors, the human-derived GV and UV radiation, will closely mimic the multifactorial pathoetiology seen in human SLE. Therefore, this mouse study can potentially provide insight into human SLE that cannot be derived from other models. This proposal is divided into 3 aims to elucidate the role of UV radiation and DNA repair in SLE pathogenesis. The first aim will seek to understand if the MSH6 GV and UV radiation leads to decreased latency and/or increased severity of lupus in mice by analyzing the onset of SLE phenotypes?such as anti-nuclear antibodies, glomerulonephritis, and dermatitis?in MSH6 GV mice un/treated with UV radiation. The second aim will seek to understand the immunological effects induced by the MSH6 GV and UV radiation. This will be determined by utilizing high-throughput sequencing and in vitro assays to elucidate how the MSH6 GV and UV radiation influences antibody diversification and the removal of autoreactive B cells. Lastly, the third aim will utilize in vitro assays to determine the binding affinity of the MSH6 variant to its cognate substrate and determine if the MSH6 GV and UV radiation promote an aberrant DNA response and cell death, which can potentially induce the production of anti-nuclear antibodies by manipulating antibody diversification and autoantigen release, respectively. The first aim will be initiated and completed during the mentored phase, and the second and third aims will be initiated during the mentored phase to gain expertise in specific techniques and completed during the independent phase. To achieve the aims of this proposal, I assembled a team of mentors with expertise in human and murine autoimmunity, inflammation, immunology, and DNA repair. This team will also provide me the guidance and tools to transition into independence and to establish a successful lab. Additional opportunities to attend and present at conferences and to mentor students and postdoctorates will be complementary for my long-term goal of establishing an independent research program. Collectively, each of these individuals and opportunities will be essential for me to gain the technical training and establish a successful research program to study the role of DNA repair and environmental stressors in autoimmunity.